Prostaglandins and related arachidonic acid metabolites are ubiquitous in animal tissues and regulate a variety of biological processes, including hormone secretion. Administered prostaglandins and inhibitors of prostaglandin synthesis modify the secretion of glucagon and insulin. The proposed project is designed to test whether in nature prostaglandins and related lipids play roles as mediators or modulators of pancreatic islet hormone secretion. The isolated, perfused rat pancreas and the micro-dissected, superfused hamster islets will serve as the models. Administered arachidonic acid and a variety of related lipids will be tested for their effects upon glucagon and insulin secretion. Also, endogenous arachidonic acid and its metabolites will be studied for their relationship to the secretion of pancreatic islet hormones: 1) Enzymes involved in various steps of arachidonic acid metabolism will be inhibited selectively by administering the appropriate pharmacological agents during periods of basal secretion of islet hormones and during various phases of secretion evoked by secretagogues; 2) the transformation of radiolabeled arachidonic acid to its metabolites in conjunction with hormone secretion will be monitored using scintillation detection and thin layer chromatographic techniques; 3) the tissue and/or effluent levels of arachidonic acid and its metabolites will be quantified using gas chromatography with detection and characterization by electron capture and mass spectrometry. Radioimmunoassays will be used also to quantify the prostaglandins formed and released upon stimulation. In all these studies the time course of arachidonate transformations as well as the quantity of the metabolites will be correlated with the time course and magnitude of glucagon and insulin secretion. The thorough definition of arachidonate transfomations in the pancreas and of the relationship between these transformations and the secretion of glucagon and insulin should enhance the understanding of the mechanisms of secretion of islet hormones and provide clues for the aberrations which could cause disease states such as diabetes.